Endocrine Abstracts

A central tenet in medicine is that disruption of homeostatic mechanisms leads to disease and effective therapy must re-establish normal physiology. The sun imposes a 24-hour periodicity to life and circadian rhythms have evolved to maintain homeostasis through the 24-hour day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which metabolically is a fast/feed cycle. The clock maintains homeostasis by synchronising metabolism to the time of feeding; for example, regulating the hormones that maintain glucose homeostasis such as insulin and the glucocorticoid, cortisol. Loss of synchrony between the clock and hormonal rhythms results in loss of homeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Loss of the cortisol rhythm in congenital adrenal hyperplasia (CAH) results in poor disease control and increased mortality. To develop chronotherapy, you need to define the drug target rhythm, create a formulation to replicate that rhythm and then prove benefit in clinical trials. The physiology of hormones is more complex than that of non-native drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations (development name Chronocort) of hydrocortisone in phase 1, 2 & 3 clinical trials. The output from this work is modified-release hydrocortisone (MRHC) capsules (tradename Efmody, Diurnal Ltd, Cardiff, UK) that replicate the cortisol diurnal rhythm and improve the disease control of CAH, the commonest hereditary form of adrenal insufficiency. Reference Whitaker MJ, Huatan H, Ross RJ. Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm. Drug Deliv Transl Res 2023;13:1-8.